Antimycotic agent

ABSTRACT

The present invention relates to a metal salt for use in pharmacy, to pharmaceutical compositions comprising it, and to the use for preparing a pharmaceutical composition for treating diseases associated with mycobionts.

The present invention relates to a metal salt for use in pharmacy, topharmaceutical compositions comprising it, and to the use for preparinga pharmaceutical composition for treating diseases associated withmycobionts.

In particular, the invention relates to the use of abis(N-organyldiazeniumdioxy) metal salt as composition for the treatmentof humans and animals infected with harmful microorganisms, inparticular mycobionts.

It is known that bis(N-organyldiazeniumdioxy) salts are fungicidallyactive. For example, DT-A 1 817 571 describes a mixture of alkali metalhydroxide and a heavy-metal salt of N-nitroso-N-cyclohexylhydroxylaminewhich is employed as fungicide in timber preservatives. Furthermore, DE24 10 603 discloses a timber-protection fungicide which comprisesheavy-metal salt derivatives of N-nitroso-N-cyclohexylhydroxylamine.

Although a large number of antimycotics, for example miconazole andclotrimazole (Canesten®, Bayer), are known, there is a constant demandfor novel antimycotic active ingredients which have novel or broaderspectra of action or which are active with respect to fungi which havedeveloped resistances to known antimycotics.

It is an object of the present invention to provide a novelpharmaceutically active, in particular antimycotically active, compoundfor use as pharmaceutical which overcomes the disadvantages of theconventional compositions.

We have found that this object is achieved by a variety ofbis(N-organyldiazeniumdioxy) metal salts which have potent antimycoticactivity against organisms capable of causing mycoses in humans oranimals.

The present invention therefore relates to a metal salt of the formula1:

in which

-   R is C₁-C₆-alkyl, C₃-C₈-cycloalkyl or aryl,-   M⁺ is a cation equivalent, and-   n is an integer from 1 to 3,-   for use as pharmaceutical.

For the purposes of the present invention, the term ‘alkyl’ encompassesstraight-chain or branched alkyl groups. These are preferablystraight-chain or branched C₁-C₄-alkyl groups. Examples of alkyl groupsare, in particular, methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl,sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl,1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyland 1-ethyl-2-methylpropyl.

The cycloalkyl group is preferably a C₅-C₇-cycloalkyl group such ascyclopentyl, cyclohexyl or cycloheptyl.

The aryl group is preferably phenyl or tolyl.

M⁺ is a cation equivalent, i.e. a monovalent cation, or that portion ofa polyvalent cation or a positively charged metal-atom-containing groupwhich corresponds to a single positive charge. For example, M⁺ is analkali metal cation such as Li⁺, Na⁺ or K⁺. Suitable bivalent cationsare, for example, Cu²⁺, Zn²⁺, Ni²⁺ and Co²⁺. Suitable trivalent cationsare, for example, Fe³⁺ and Al³⁺. Suitable monovalentmetal-atom-containing groups are, for example, tin-containing groups ofthe formula R^(a)R^(b)R^(c)Sn⁺ in which R^(a), R^(b) and R^(c)independently of one another are C₁₋₆-alkyl radicals. R¹, R² and R³ arepreferably butyl, i.e. the metal-atom-containing group is (C₄H₉)₃Sn⁺.

Preferred cations are K⁺, Cu²⁺ and Al³⁺. Especially preferred as metal Mis copper.

Preferred radicals R are C₅- and C₆-alkyl or C₅- and C₆-cycloalkylgroups, in particular cyclohexyl.

Preferred metal salts are N-cyclohexyldiazeniumdioxypotassium andtris(N-cyclohexyldiazeniumdioxy)aluminum.

An especially preferred embodiment relates to the use according to theinvention of bis(N-cyclohexyldiazeniumdioxy)copper of the formula 2:

The invention furthermore relates to a pharmaceutical compositioncomprising at least one compound of the formula 1 as defined above andat least one or more pharmaceutically acceptable carrier(s) and/oradditive(s).

The invention also relates to methods for the treatment of diseasesassociated with mycobionts, in which an antimycotically active amount ofa compound of the formula 1 according to the invention is administeredto a person or to an animal requiring such a treatment.

Mycobionts, also termed fungi or Mycota, are eucaryotic organisms whichgrow under aerobic conditions and obtain the energy required byoxidizing organic substances. Some representatives, for example yeasts,are facultatively viable under anaerobic conditions, obtaining theirenergy by fermentation processes. The representatives of the mycobiontsinclude, for example, yeasts or budding fungi, molds, dimorphic fungiand dermatophytes.

Mycoses are diseases caused by fungi; they may occur locally orgenerally. They occur, inter alia, when the immune system iscompromised, for example during therapies involving antibiotics orcytostatics, during the administration of steroids or hormones,following irradiation, during parenteral feeding, or during malignantdiseases, endocrinopathies or immunodeficiences. In the case of systemicmycoses, specific organs are infected preferentially. Dermatomycoses,for example, are diseases where specific fungal species, in particulardermatophytes and yeasts, infect the skin and/or its cutaneousappendages. The fungi penetrate the skin, hair, hair folicles andfinger- or toenails and cause symptoms such as vesiculation,exfoliation, skin fissures, and erosion, in most cases in conjunctionwith pruritus and/or allergic eczema. While dermatomycoses affect almostexclusively the skin, hair and nails, mycoses caused by yeasts may alsospread to mucus membranes and internal organs.

Surprisingly, it has now been found that the metal salts of the formula1, in particular the copper salts thereof, have potent antimycoticactivity. An example of an especially preferred compound which can beused in accordance with the invention isbis(N-cyclohexyldiazeniumdioxy)copper. The spectrum of action of thecompounds which can be used in accordance with the invention extends toyeasts, dermatophytes, molds, Pityrosporum ovale and biphasic fungi. Thecompounds according to the invention can therefore be employedsuccessfully as active substance for the treatment of a large number oflocal and systemic mycoses in humans and animals. The active ingredientsaccording to the invention are particularly effective in the treatmentof dermatomycoses caused by Trichophyton rubrum, Trichophytonmentagrophytes and other Trichophyton species, Microsporum canis,Epidermophyton floccosum and Scopulariopsis brevicaulis, and candidosescaused by Candidai tropicalis, Candida albicans, Candida glabrata,Candida parapsilosis and further Candida species.

Diseases in which the compounds according to the invention can beemployed are, for example, disorders of the immune system, HIVinfections, AIDS, skin diseases, diseases of the airways and thepharynx, systemic infections, local infections, for example of the skin,the hair or the nails, infections of the mucus membranes, otitis,pharyngitis, pneumonia, pyelonephritis, cystitis, endocarditis,bronchitis and arthritis.

The present invention also includes pharmaceutical preparationscomprising one or more active ingredients according to the invention andone or more nontoxic inert pharmaceutically acceptable carrier materialsand, if appropriate, one or more nontoxic inert pharmaceuticallyacceptable adjuvants and one or more nontoxic inert pharmaceuticallyacceptable additives.

Pharmaceutically acceptable materials are the substances which, as isknown, can be used in the pharmaceutical sector, the food technologysector and related fields, in particular the substances listed inspecialist pharmacopeias and whose properties are no obstacle tophysiological applications.

The bis(N-organyldiazeniumdioxy) metal salts which are employed inaccordance with the invention as antimycotic active ingredients areprepared by customary methods known to the skilled worker.

For example, the active ingredients which can be used in accordance withthe invention can be formulated as tablets, coated tablets, capsules,pills, granules, suppositories, solutions, suspensions and emulsions,pastes, ointments, gels, creams, lotions, powder or sprays.

Suitable carrier materials for tablets, coated tablets, capsules, pillsand granules are customary fillers and extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid.

Suitable carrier materials for suppositories, solutions, suspensions,emulsions, pastes, ointments, gels, creams and lotions are selected fromwater, hydrophilic components and hydrophobic components, and mixturesof these. Suitable hydrophilic components in excipients are, forexample, mono-, di- or polyhydric alcohols having preferably 1 to 8carbon atoms, such as ethanol, n-propanol, isopropanol, propyleneglycol, glycerol, sorbitol and the like. Suitable hydrophobic componentsin excipients are, for example, oily or fatty components such as solidand liquid paraffins; Vaseline; natural fats and oils such as castoroil, soya oil, corn oil, cottonseed oil, peanut oil, olive oil,sunflower oil, sesameseed oil, avocado oil, cocoa butter, almond oil,peach kernel oil, codliver oil, lard, spermaceti, spermaceti oil, spermoil, wheatgerm oil, macadamia nut oil, oil of evening primrose, jojobaoil; fatty alcohols such as lauryl alcohol, myristyl alcohol, cetylalcohol, stearyl alcohol, oleyl alcohol; fatty acids such as myristicacid, stearic acid, palmitic acid, oleic acid, linoleic acid, linolenicacid; waxes such as beeswax, carnauba wax, candelilla wax, spermacetiand mixtures of these.

Suitable carrier materials for powders or sprays are, for example,lactose, talc, silicic acid, aluminum hydroxide, calcium silicate andpolyamide powder, or mixtures of these. Sprays may additionally comprisethe customary propellants, for example, fluorochlorohydrocarbons.

The preparations according to the invention may furthermore comprise oneor more nontoxic, inert pharmaceutically acceptable adjuvants. These cantake the form of solid, semisolid or liquid materials which act asvehicles, carriers or constituents for the active ingredient. Examplesof suitable adjuvants are lubricants, wetting agents, emulsifiers,suspending agents, preservatives, adsorbents, antioxidants,antiinflammatories, binders, chelating agents, emulsion stabilizers,humectants, film formers, gellants, odor-masking agents, resins,hydrocolloids, solvents, solubilizers, solution retardants, neutralizingagents, penetrants, pigments, quaternary ammonium compounds, resorbents,superfatting agents, excipients for ointments, creams or oils, siliconederivatives, stabilizers, sterilants, propellants, desiccants,opacifying agents, thickeners, waxes, plasticizers, white oils and otherdiluents, fillers and formulation auxiliaries of any type. If desired,the adjuvants and/or further additives such as odor- and/orflavor-improving additions or colorants are admixed in a manner withwhich the skilled worker is familiar.

The tablets, coated tablets, capsules, pills or granules can be providedwith the customary coatings and coats which, if desired, compriseopacifying agents. They may also be present in microencapsulated form orbe composed in such a way that they release the active ingredient(s)only, or preferentially, in a particular part of the intestinal tract,if appropriate in a sustained manner. Embedding materials which can beused in this context are, for example, polymeric substances and waxes.

For parenteral administration, solutions or emulsions which can be usedin accordance with the invention may be present in sterile andblood-isotonic form.

The pharmaceutical preparations according to the invention can beformulated in a variety of dose units. The dose units may correspond,for example, to a unit dose, a fraction of a unit dose or a multiplethereof. Examples of dose units are one, two, three or four unit dosesor half, a third or a quarter of a unit dose. A unit dose preferablycomprises an amount of active ingredient which corresponds to a dailydose or to half, a third or a quarter thereof.

The therapeutically active compounds in the above-mentionedpharmaceutical preparations should be present in a concentration of fromapproximately 0.0001 to 99.5% by weight, preferably from 0.001 to 95% byweight, specifically from 0.01 to 50% by weight, based on the totalmixture. Advantageously, a therapeutic activity in a variety of mycosesis evidenced even at very low active ingredient concentrations such as0.00015% by weight. In addition to the active ingredients according tothe invention, the preparations may also comprise further pharmaceuticalactive ingredients.

The pharmaceutical preparations according to the invention are preparedin the customary manner by method known to the skilled worker.

The present invention also includes a method of treating diseasesassociated with mycobionts. In this context, an antimycotically activeamount of the active ingredient according to the invention isadministered to a person or an animal reuqiring such a treatment. Theactive ingredient or the pharmaceutical preparation can be administeredlocally, orally, parenterally, intraperitoneally and/or rectally,preferably orally or locally.

In the case of systemic administration, it has been generally provedadvantageous to administer the active ingredient(s) according to theinvention in a total amount of from approximately 0.3 to 80 mg/kg bodyweight, preferably 3 to 15 mg/kg body weight, per 24 hours. The amountof active ingredient may be administered at once or split into severalsingle doses. In some cases, however, it may be necessary to deviatefrom the abovementioned proposed dosages, viz. as a function of the bodyweight, the nature and severity of the disease, or the type ofpreparation or of pharmaceutical form. Thus, it may suffice in somecases to employ a smaller amount of active ingredient, while in othercases the abovementioned amount of active ingredient may be exceeded.The amount which is most suitable in each case can be determined readilyby the skilled worker.

The invention also relates to a composition in the form of a commercialpack with at least one composition based on a metal salt as definedabove, together with instructions for therapeutical use.

The invention also relates to the use of a metal salt of the formula 1where R is C₁-C₆-alkyl, C₃-C₈-cycloalkyl or aryl, M⁺ is a cationequivalent and n is an integer from 1 to 3, for the preparation of apharmaceutical composition for treating diseases associated withmycobionts.

If the active ingredient according to the invention is used as feedadditive, it may be administered in the customary manner together withthe feed or the feed product or the drinking water.

The activity of the active ingredient according to the invention asantimycotic was studied in an in-vitro agar incorporation test. To thisend, various samples of mycobionts were grown in a nutrient medium ofSabouraud agar and supplemented with various amounts of activeingredient. The active ingredient concentration in the medium was in therange from 1 to 100 ppm. Incubation times were between 1 and 21 days.The experiments with yeasts of the Candida type revealed effectivegrowth inhibition at an active ingredient concentration of 50 ppm and anincubation time of from 2 to 5 days. Experiments with dermatophytecultures revealed effective growth inhibition at an active ingredientconcentration in the range from 15 to 40 ppm after an incubation time of1 to 3 weeks.

EXAMPLES Example 1

Use of bis(N-cyclohexyldiazeniumdioxy)copper for inhibiting the growthof various Candida species.

The activity of the compound according to the invention as agent forinhibiting the growth of various types of yeasts was studied in an agarincorporation test. The nutrient medium used was Sabouraud agar. Severalsamples of each of the yeast types below, which were isolated directlyfrom diseased patients, were tested:

-   a) Candida tropicalis-   b) Candida albicans-   c) Candida glabrata-   d) Candida parapsilosis.

The inoculum suspensions had a density of 10⁷ colony-forming units perml. The cultures were supplemented withbis(N-cyclohexyldiazeniumdioxy)copper in such an amount that an endconcentration of 25 or 50 ppm was obtained. The cultures weresubsequently incubated at 30° C., and the growth of the isolates wasassessed after an incubation period of 2 to 5 days.

At an active ingredient concentration of 25 ppm, all of the isolatestested were still growing after an incubation period of 2 and 5 days. Atan active ingredient concentration of 50 ppm, however, no growth tookplace.

Example 2

Use of bis(N-cyclohexyldiazeniumdioxy)copper for inhibiting the growthof various species of dermatophytes.

The activity of the compound according to the invention for inhibitingthe growth of the dermatophyte cultures below was studied in an agarincorporation test as described in Example 1. The active ingredientconcentration in the samples amounted to 2.5, 5, 10, 15, 20, 25, 30, 35,40, 45 and 50 ppm. The isolates were studied after an incubation periodof 7, 14 and 21 days, and their growth was determined. The activeingredient concentrations at which effective growth inhibition wasobserved are shown in the table which follows. Effective activeingredient Dermatophyte concentration [ppm] Incubation period 7 days 14days 21 days Trichlorophyton 15 15 15 rubrum Trichophyton 30 30 30mentagrophytes Microsporum canis ≦10 15 15 Epidermophyton 15 20 20floccosum Scopulariopsis 25 35 40 brevicaulis

The most effective inhibition of dermatophyte growth was observed afteran incubation period of 21 days at a concentration of from 15 to 40 ppm.

1. A metal salt of the formula 1

in which r is c₁-C₆-alkyl, c₃-C₈-cycloalkyl or aryl, M⁺ is a cationequivalent, and n is an integer from 1 to 3, for use as pharmaceutical.2. A metal salt as claimed in claim 1 in which M is a bivalent metalcation selected from the group consisting of copper, zinc, nickel andcobalt.
 3. A metal salt as claimed in claim 2, in which the metal cationis the copper cation.
 4. A metal salt as claimed in claim 1, which isbis(N-cyclohexyldiazeniumdioxy)copper.
 5. A metal salt as claimed inclaim 1 for treating diseases associated with mycobionts.
 6. Apharmaceutical composition comprising at least one compound of theformula 1 as defined in claim 1 and at least one or morepharmaceutically acceptable carrier(s) and/or additive(s).
 7. Acomposition in the form of a commercial pack with at least onecomposition based on a metal salt as defined in claim 1, together withinstructions for therapeutic use.
 8. A method of treating diseasesassociated with mycobionts, in which an antimycotically active amount ofa compound of the formula 1 as defined in claim 1 is administered to aperson or to an animal requiring such a treatment.
 9. The metal salt ofthe formula 1 in which R is C₁-C₆-alkyl, C₃-C₈-cycloalkyl or aryl, M⁺ isa cation equivalent and n is an integer from 1 to 3 for the preparationof a pharmaceutical composition for treating diseases associated withmycobionts.